CN117417325A - 氘代1,2,4-三唑类Apelin受体激动剂药物及用途 - Google Patents
氘代1,2,4-三唑类Apelin受体激动剂药物及用途 Download PDFInfo
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- 108091008803 APLNR Proteins 0.000 title claims abstract description 22
- 239000000018 receptor agonist Substances 0.000 title claims abstract description 18
- 229940044601 receptor agonist Drugs 0.000 title claims abstract description 18
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical class C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 title claims abstract description 12
- 102000016555 Apelin receptors Human genes 0.000 title claims abstract 5
- 239000003814 drug Substances 0.000 title claims description 20
- 229940079593 drug Drugs 0.000 title description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
- 150000003839 salts Chemical class 0.000 claims description 15
- -1 Deuterated 1,2, 4-triazole compound Chemical class 0.000 claims description 14
- 150000001875 compounds Chemical class 0.000 claims description 11
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 claims description 3
- 229910052805 deuterium Inorganic materials 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 239000002674 ointment Substances 0.000 claims description 2
- 239000006187 pill Substances 0.000 claims description 2
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- 239000000829 suppository Substances 0.000 claims description 2
- 239000006188 syrup Substances 0.000 claims description 2
- 235000020357 syrup Nutrition 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 150000003840 hydrochlorides Chemical class 0.000 claims 1
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- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 claims 1
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- 150000003013 phosphoric acid derivatives Chemical class 0.000 claims 1
- 102100030949 Apelin receptor Human genes 0.000 description 19
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- BWVPHIKGXQBZPV-QKFDDRBGSA-N apelin Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N1[C@H](C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=2NC=NC=2)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=2NC=NC=2)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CCSC)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(O)=O)CCC1 BWVPHIKGXQBZPV-QKFDDRBGSA-N 0.000 description 10
- 102000018746 Apelin Human genes 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
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- 239000000243 solution Substances 0.000 description 7
- 238000010189 synthetic method Methods 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
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- 231100000331 toxic Toxicity 0.000 description 4
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- 206010028289 Muscle atrophy Diseases 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
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- 238000010172 mouse model Methods 0.000 description 2
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- 201000000585 muscular atrophy Diseases 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
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- 230000001105 regulatory effect Effects 0.000 description 2
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- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- HQBJSEKQNRSDAZ-WFGJKAKNSA-N 2,6-bis(trideuteriomethoxy)aniline Chemical compound NC1=C(C=CC=C1OC([2H])([2H])[2H])OC([2H])([2H])[2H] HQBJSEKQNRSDAZ-WFGJKAKNSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- WRUMPFKEBDWTRU-UHFFFAOYSA-N B(F)(F)F.C/C(=C/C)/[K] Chemical compound B(F)(F)F.C/C(=C/C)/[K] WRUMPFKEBDWTRU-UHFFFAOYSA-N 0.000 description 1
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
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- 206010061218 Inflammation Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 102000011990 Sirtuin Human genes 0.000 description 1
- 108050002485 Sirtuin Proteins 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003712 anti-aging effect Effects 0.000 description 1
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- 238000003556 assay Methods 0.000 description 1
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- 102000000072 beta-Arrestins Human genes 0.000 description 1
- 108010080367 beta-Arrestins Proteins 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
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- 230000036542 oxidative stress Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- HBCQSNAFLVXVAY-UHFFFAOYSA-N pyrimidine-2-thiol Chemical compound SC1=NC=CC=N1 HBCQSNAFLVXVAY-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000036454 renin-angiotensin system Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- CITILBVTAYEWKR-UHFFFAOYSA-L zinc trifluoromethanesulfonate Chemical compound [Zn+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F CITILBVTAYEWKR-UHFFFAOYSA-L 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
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- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
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Abstract
本发明公开了一种氘代1,2,4‑三唑Apelin受体激动剂,如下式Ⅰ所示,本发明涉及氘代1,2,4‑三唑Apelin受体激动剂、其药物组合物及用途。
Description
技术领域
本发明属于生物医药领域,具体涉及氘代1,2,4-三唑类Apelin受体激动剂药物及用途。
背景技术
Apelin是G蛋白偶联受体APJ的内源性配体,在多种器官中广泛表达。近年来的研究表明,Apelin/APJ在衰老过程中起着重要作用。Apelin和APJ受体的表达随年龄的增加而下调。在小鼠模型中,Apelin和APJ敲除会加速衰老,而Apelin修复会增强活力,使行为和昼夜节律表型恢复活力。此外,衰老的Apelin基因敲除小鼠会出现与收缩功能障碍相关的心脏收缩性进行性损伤。在衰老过程中,Apelin对维持心脏收缩力至关重要。此外,Apelin/APJ系统似乎参与调节肾素-血管紧张素-醛固酮系统(RAAS)、细胞凋亡、炎症和氧化应激,从而促进衰老。同样,Apelin/APJ系统调节自噬、干细胞和sirtuin家族,从而有助于抗衰老。
BGE-105是抗衰老公司BioAge Labs开发的一类Apelin受体激动剂,目前处于临床Ⅰb,该临床试验收集肌肉生物标志物数据,在老年小鼠模型中,BGE-105显著改善了由于肢体固定导致的肌肉萎缩,防止肌肉功能随着年龄增长而丧失,并诱导了肌肉再生的生物标志物,具备预防肌肉萎缩和改善老年人肌肉功能的潜力。
氘代药物,既将药物分子的一个或多个碳氢键用碳氘键替代的新药物分子,可以通过改善原有药物的药代动力学性质,进而克服药物原有的易于代谢、副作用较大等缺陷。
本发明为多位点氘代1,2,4-三唑类Apelin受体激动剂药物,相对于单位点氘代化合物,可以进一步改善Apelin受体激动剂BGE-105的药代动力学性质,降低给药剂量和可能的毒副作用。
发明内容
本发明提供的多位点氘代1,2,4-三唑类Apelin受体激动剂药物BGE-105化合物及其药学上可接受的盐,可以进一步改善Apelin受体激动剂药物BGE-105的氘代1,2,4-三唑类化合物及其药学上可接受的盐的药代动力学性质,降低给药剂量和可能的毒副作用。
为了实现上述目的,如本发明所述一种如下式Ⅰ所示的Apelin受体激动剂药物BGE-105的氘代1,2,4-三唑类化合物及其药学上可接受的盐:
其中,R1, R2, R3, R4, R5独立地选自H或氘,且R1, R2, R3, R4, R5不同时为H。
进一步本发明所述Apelin受体激动剂药物BGE-105的氘代1,2,4-三唑类化合物,其结构为:
。
本发明所述Apelin受体激动剂药物的氘代1,2,4-三唑类化合物及其药学上可接受的盐,其药学上可接受的盐选自甲磺酸盐、马来酸盐、盐酸盐或磷酸盐。
本发明所述的氘代1,2,4-三唑类化合物及其药学上可接受的盐,包括其在制备Apelin受体激动剂药物抑制剂药物中的应用。
本发明所述的氘代1,2,4-三唑类化合物及其药学上可接受的盐,包括氘代1,2,4-三唑类化合物及其药学上可接受的盐作为活性成分和药学上可接受的载体组成。
本发明所述的氘代1,2,4-三唑类化合物及其药学上可接受盐的药物组合物,所述药物组合物选自胶囊剂、散剂、片剂、颗粒剂、丸剂、注射剂、糖浆剂、口服液、吸入剂、软膏剂、栓剂或贴剂。有益效果:与现有技术相比,本发明具有如下优点:
本发明提供一类氘代1,2,4-三唑类Apelin受体激动剂药物,进一步改善Apelin受体激动剂药物的药代动力学性质,降低给药剂量和可能的毒副作用。
具体实施方式
以下结合实施例对本发明作进一步说明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
实施例1
合成方法
向原料1-A(5 mmol)、(Z)-丁-2-烯-2-基三氟硼酸钾(7.5 mmol)、磷酸钾(10mmol)、三环己基膦(20%mol)和Pd2(dba)3(10%mol)用1, 4-二氧六环/H2O(1:2)溶解,氮气保护后,置于100度条件下搅拌反应过夜,TLC检测反应完全,过滤不溶物,浓缩经柱层析纯化,制得中间体1-B。
将嘧啶-2-硫醇(5 mmol)用DCM溶解,再加入硫酰氯(5 mmol),0度条件下搅拌1小时,移至室温后,再逐滴加入中间体1-B(5 mmol)的DCM溶液,继续反应2小时。TLC检测反应完全,加入碳酸氢钠饱和溶液进行萃取,有机相浓缩后经柱层析纯化得中间体1-C。
将中间体1-C(5 mmol)溶于二氯甲烷中,并加入间氯过氧苯甲酸(10 mmol)。室温下搅拌过夜,加入硫代硫酸钠饱和溶液淬灭,并用乙酸乙酯萃取。浓缩过柱得中间体1-D。
将1-D(5 mmol)用甲醇溶解,加入碳酸钾(10 mmol),室温反应过夜,浓缩得中间体1-E。
向1-E(5 mmol)的水溶液中加入乙酸钾(5 mmol)和酰氨基过氧基单硫酸(10mmol),室温反应24小时,TLC监测反应完全,水相用乙酸乙酯(10 mL*2)萃取,水(20 mL*2)洗,饱和食盐(20 mL)水洗无水硫酸钠干燥,浓缩柱层析,得中间体1-F。
向中间体1-F(5 mmol)的乙醇溶液(8 mL)中加入三氟甲烷磺酸锌(0.25 mmol)、(R)-(-)-4, 12-双(二苯膦基)[2.2]对环芳烷(1,5-环辛二烯)铑四氟硼酸盐,氢气气氛下,室温反应3小时,TLC检测反应完全,过滤,减压浓缩,柱层析得中间体1-G。
将原料1-H(5 mmol)用二氯甲烷溶解,和三乙烯二胺(15 mmol)用10 mL 丙酮溶解,室温条件下搅拌15分钟,待固体溶解后,分批滴入10 mL的二硫化碳。 滴加过程中,溶液中产生大量固体,滴加完毕,继续充分搅拌两个小时后TLC监测反应完全。停止搅拌,过滤,滤饼用石油醚洗两次,收集滤饼并干燥。之后将上述得到的固体,溶于10 mL氯仿中,0 0C条件下搅拌。将三光气(1.8 mmol)溶于5 mL氯仿中,缓慢滴入上述反应液中,滴加完毕,将反应液移植室温搅拌过夜。TLC监测反应完全。过滤掉溶液中不溶物,旋干溶剂,经柱层析纯化,用乙酸乙酯/石油醚(1:3)过得无色液体得1-I。
将中间体1-I(3 mmol)和1-G(3 mmol)用乙腈(10mL)溶解,再加入碳酸铯(4mmol),氮气保护条件下搅拌过夜,浓缩后得中间体1-J。
将中间体1-K(3 mmol)和水合肼(6 mmol)用乙醇(10mL)溶解,升温至80℃搅拌16小时。浓缩后,加入石油醚搅拌得中间体1-L。
将中间体1-J(5 mmol)、1-J(5 mmol)和硝酸银(6 mmol)并用氮气保护,继续反应2小时,加入3mL三氟乙酸,于100度搅拌反应过夜,TLC检测反应完全,过滤经柱层析得实施例1。1H NMR (500 MHz, Chloroform-d) δ 8.97 (d, J = 1.2 Hz, 1H), 8.22 (d, J = 1.3Hz, 1H), 7.91 (t, J = 1.3 Hz, 1H), 7.53 (s, 2H), 7.16 (t, J = 7.5 Hz, 1H),6.87 (d, J = 7.5 Hz, 2H), 4.01 (s, 1H), 3.85 (s, 6H), 3.49 (s, 1H), 2.32 (s,3H), 1.49 (d, J = 2.8 Hz, 3H), 1.20 (d, J = 2.8 Hz, 3H).
实施例2
参照实施例1的合成方法,把1-A替换成2-氯-5-甲基嘧啶-4,6-d2,可制得实施例2。1H NMR (500 MHz, Chloroform-d) δ 8.97 (d, J = 1.2 Hz, 1H), 8.22 (d, J = 1.3Hz, 1H), 7.91 (t, J = 1.3 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 6.87 (d, J = 7.5Hz, 2H), 4.25 (s, 1H), 3.85 (s, 6H), 3.46 (s, 1H), 2.32 (s, 3H), 2.09 (d, J =2.8 Hz, 3H), 1.27 (d, J = 2.8 Hz, 3H).
实施例3
参照实施例1的合成方法,将1-K替换成5-(甲基-d3)烟酸甲酯可制得实施例3。1HNMR (500 MHz, Chloroform-d) δ 9.02 (d, J = 1.2 Hz, 1H), 8.32 (s, 2H), 7.79 –7.56 (m, 2H), 7.16 (t, J = 7.5 Hz, 1H), 6.87 (d, J = 7.5 Hz, 2H), 4.01 (s,1H), 3.85 (s, 6H), 3.48 (s, 1H), 2.23 (s, 3H), 1.49 (d, J = 2.8 Hz, 3H), 1.20(d, J = 2.8 Hz, 3H).
实施例4
参照实施例1的合成方法,把中间体1-H替换成2,6-双(甲氧基-d3)苯胺,可制得实施例4。1H NMR (500 MHz, Chloroform-d) δ 8.97 (d, J = 1.2 Hz, 1H), 8.32 (s,2H), 8.22 (d, J = 1.3 Hz, 1H), 7.91 (t, J = 1.3 Hz, 1H), 7.24 (t, J = 7.4 Hz,1H), 6.87 (d, J = 7.5 Hz, 2H), 4.01 (s, 1H), 3.47 (s, 1H), 2.32 (s, 3H), 2.23(d, J = 2.8 Hz, 3H), 1.20 (d, J = 2.8 Hz, 3H).
实施例5
参照实施例1的合成方法,可制得实施例5。1H NMR (500 MHz, Chloroform-d) δ8.97 (d, J = 1.2 Hz, 1H), 8.32 (s, 2H), 8.22 (d, J = 1.3 Hz, 1H), 7.91 (t, J= 1.3 Hz, 1H), 4.01 (s, 1H), 3.80 (s, 6H), 3.47 (s, 1H), 2.32 (s, 3H), 2.23(d, J = 2.8 Hz, 3H), 1.20 (d, J = 2.8 Hz, 3H).
实施例6
参考实施例1的合成方法,可制得实施例6. 1H NMR (500 MHz, Chloroform-d) δ8.97 (d, J = 1.2 Hz, 1H), 8.22 (d, J = 1.3 Hz, 1H), 7.91 (t, J = 1.3 Hz, 1H),7.16 (t, J = 7.5 Hz, 1H), 6.87 (d, J = 7.5 Hz, 2H), 4.25 (s, 1H), 3.85 (s,6H), 3.46 (s, 1H), 2.32 (d, J = 2.8 Hz, 3H), 1.27 (d, J = 2.8 Hz, 3H).
实施例7
参考实施例1的合成方法,把中间体11替换成4-溴-5-(甲基-d3)-甲基-3-(甲基-d3)-1H-吡唑-1-甲酸叔丁酯,可制得实施例7. 1H NMR (500 MHz, Chloroform-d) δ 9.02(d, J = 1.2 Hz, 1H), 7.72 – 7.54 (m, 2H), 7.16 (t, J = 7.5 Hz, 1H), 6.87 (d,J = 7.5 Hz, 2H), 4.25 (s, 1H), 3.85 (s, 6H), 3.46 (s, 1H), 2.44 (d, J = 2.8Hz, 2H), 1.27 (d, J = 2.8 Hz, 3H).
实施例8
参考实施例1的合成方法,可制得实施例8. 1H NMR (500 MHz, Chloroform-d) δ8.97 (d, J = 1.2 Hz, 1H), 8.22 (d, J = 1.3 Hz, 1H), 7.91 (t, J = 1.3 Hz, 1H),7.24 (t, J = 7.4 Hz, 1H), 6.87 (d, J = 7.5 Hz, 2H), 4.25 (s, 1H), 3.46 (s,1H), 2.32 (d, J = 2.8 Hz, 3H), 1.27 (d, J = 2.8 Hz, 3H).
实施例9
参考实施例1的合成方法,可制得实施例9。1H NMR (500 MHz, Chloroform-d) δ8.97 (d, J = 1.2 Hz, 1H), 8.32 (s, 2H), 8.22 (d, J = 1.3 Hz, 1H), 7.91 (t, J= 1.3 Hz, 1H), 4.01 (s, 1H), 3.47 (s, 1H), 2.32 (s, 3H), 2.23 (d, J = 2.8 Hz,3H), 1.20 (d, J = 2.8 Hz, 3H).
实施例10
参考实施例1的合成方法,可制得实施例10. 1H NMR (500 MHz, Chloroform-d)δ 9.02 (d, J = 1.2 Hz, 1H), 8.32 (s, 2H), 7.81 – 7.35 (m, 2H), 4.01 (s, 1H),3.47 (s, 1H), 2.23 (d, J = 2.8 Hz, 3H), 1.20 (d, J = 2.8 Hz, 3H).
实施例11
参考实施例1的合成方法,可制得实施例11. 1H NMR (500 MHz, Chloroform-d)δ 9.02 (d, J = 1.2 Hz, 1H), 7.78 – 7.49 (m, 2H), 4.25 (s, 1H), 3.44 (s, 1H),2.46 (d, J = 2.8 Hz, 3H), 1.27 (d, J = 2.8 Hz, 3H).
实施例12
参考实施例1的合成方法,可制得实施例12. 1H NMR (500 MHz, Chloroform-d)δ 9.02 (d, J = 1.1 Hz, 1H), 8.32 (s, 2H), 7.72 – 7.52 (m, 2H), 7.24 (t, J =7.4 Hz, 1H), 6.87 (d, J = 7.5 Hz, 2H), 4.01 (s, 1H), 3.47 (s, 1H), 2.23 (d, J= 2.8 Hz, 3H), 1.20 (d, J = 2.8 Hz, 3H).
试验例1:PathHunter β-arrestin eXpress GPCR测定
将稳定表达人源Apelin受体的CHO细胞加入96孔板中,并在37℃条件下孵育过夜。将待测化合物用DMSO溶解并3倍稀释到对应测试浓度。加入待测化合物并与细胞在37℃条件下共孵育三小时。加入PathHunter检测溶液后,孵育30分钟后在485和525nm波长上检测荧光强度。
表1、化合物EC50值
化合物编号 | EC50 (pM) |
实施例1 | 66 |
实施例2 | 78 |
实施例3 | 82 |
实施例4 | 73 |
实施例5 | 59 |
实施例6 | 73 |
实施例8 | 64 |
实施例9 | 84 |
实施例10 | 92 |
实施例11 | 82 |
实施例12 | 73 |
BGE-105 | 106 |
由此可见,表1数据显示实施例化合物相比于阳性药BGE-105活性均有不同程度的提升,增益显著。
试验例2:化合物的药代动力学实验
实施例和BGE-105使用DMSO/solutol/water(10/10/80)溶解制成澄清溶液,口服给药。口服给药后的5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 5 h, 8 h, 12 h, 16 h,24 h,从眼底静脉丛连续取血0.5 mL肝素管中。将样品在8000 r,4℃条件下离心10 min后,取上层血浆0.15 mL,-20℃条件下保存,之后进行LC-MS/MS分析。数据通过WinNolin非房室模型分析,得到关键药代动力学参数。
(一)实验结果
表2、药代动力学参数
Parameter | BGE-105 | 实施例2 | 实施例3 |
Tmax (h) | 1.2 ± 0.3 | 2.2 ± 1.2 | 2.6 ± 1.1 |
t1/2 (h) | 8 ± 3.2 | 14 ± 7.1 | 13 ± 8.2 |
Cmax (ng/mL) | 342 ± 93 | 412 ± 113 | 368 ± 108 |
Parameter | 实施例5 | 实施例7 | 实施例8 |
Tmax (h) | 2.1 ± 0.6 | 3.5 ± 1.1 | 2.4 ± 1.6 |
t1/2 (h) | 12 ± 6.1 | 9 ± 5.4 | 9.6 ± 3.8 |
Cmax (ng/mL) | 455 ± 98 | 456 ± 103 | 588 ± 169 |
Parameter | 实施例9 | 实施例10 | 实施例11 |
Tmax (h) | 1.9 ± 0.8 | 1.8 ± 0.9 | 1.9 ± 1.0 |
t1/2 (h) | 11 ± 6.8 | 19 ± 6.9 | 15 ± 5.8 |
Cmax (ng/mL) | 499 ± 187 | 512 ± 233 | 466 ± 144 |
相对于BGE-105,表2中实施例化合物口服给药的半衰期提高明显,可以有效改进给药剂量,从而降低高剂量给药的毒副作用。
最后有必要说明的是,以上对本发明的具体实施例进行了详细描述,但其只作为范例,本发明并不限制于以上描述的具体实施例。对于本领域技术人员而言,任何对本发明进行的等同修改和替代也都在本发明的范畴之中。因此,在不脱离本发明的精神和范围下所作的均等变换和修改,都应涵盖在本发明的范围内。
Claims (6)
1.一种式Ⅰ所示氘代1,2,4-三唑类化合物及其药学上可接受的盐,其特征在于所述结构如下:
,
其中,R1, R2, R3, R4, R5独立地选自H或氘,且R1, R2, R3, R4, R5不同时为H。
2.根据权利要求1所述的氘代1,2,4-三唑类化合物及其药学上可接受的盐,其特征在于所述化合物选自以下结构:
。
3.根据权利要求1或2所述的氘代1,2,4-三唑类化合物及其药学上可接受的盐,其特征在于所述药学上可接受的盐选自甲磺酸盐、马来酸盐、盐酸盐或磷酸盐。
4.一种根据权利要求1或2所述的氘代1,2,4-三唑类化合物及其药学上可接受的盐在制备Apelin受体激动剂药物中的应用。
5.根据权利要求1或2所述氘代1,2,4-三唑类化合物及其药学上可接受盐的药物组合物,其特征在于,所述药物组合物由所述氘代1,2,4-三唑类化合物及其药学上可接受的盐作为活性成分和药学上可接受的载体组成。
6.根据权利要求5所述的氘代1,2,4-三唑类Apelin受体激动剂的药物组合物,其特征在于,所述药物组合物选自胶囊剂、散剂、片剂、颗粒剂、丸剂、注射剂、糖浆剂、口服液、吸入剂、软膏剂、栓剂或贴剂。
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